Irinotecan: toward clinical end points in drug development.

The objective response rate is the initial method to assess the activity of a novel anticancer agent. Response rates may not characterize a new agent's clinical benefit, however, especially if moderate to severe toxicity may be associated with treatment. Clinical end points, such as improvement in survival or relief of disease-related symptoms, provide clinicians with a more rational basis for selecting therapies. Irinotecan (CPT-11 [Camptosar]) was introduced into clinical practice based primarily on its consistent phase II activity (response rates of 13.3% to 21.7% in patients with advanced colorectal cancer refractory to 5-fluorouracil [5-FU]). Two recently presented, randomized, phase III trials have examined irinotecan's impact on clinical end points of survival, quality of life, tolerability, and control of disease-related symptoms in 5-FU-refractory colorectal cancer patients. The first trial prospectively compared irinotecan and best supportive care (BSC) to BSC alone in patients with 5-FU-resistant metastatic colorectal cancer. Irinotecan-treated patients had significantly prolonged survival, improved quality of life, and better control of disease-related symptoms. The second trial compared irinotecan to infusional 5-FU schedules in colorectal cancer patients whose tumors had progressed within 3 months of prior 5-FU. Patients treated with irinotecan lived significantly longer than those given infusional 5-FU and had a comparable quality of life. These randomized trials demonstrate an evolution in our understanding of the clinical utility of irinotecan.